Is IP6K2 p.Leu33Phe (c.97C>T) pathogenic?

IP6K2 p.Leu33Phe (c.97C>T) is classified Uncertain significance in IP6K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.7211); Ultra-rare (popmax 0.0148%, afr).

How common is IP6K2 p.Leu33Phe (c.97C>T) in the general population?

IP6K2 p.Leu33Phe (c.97C>T) is ultra-rare (popmax 0.0148%, afr) (gnomAD).

What do computational predictors say about IP6K2 p.Leu33Phe (c.97C>T)?

AlphaMissense predicts likely pathogenic (score 0.7211) — an in-silico prediction, not a clinical call.

IP6K2 p.Leu33Phe

c.97C>T · rs375230535 · VCV2591309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7211 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7211	likely pathogenic
REVEL	0.499	indeterminate
SaProt	LLR -3.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 7,015 bp · p 5.9e-19 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0148% African / African-American · 11/74,466 alleles

Filtering AF 0.0082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00637%

Overall 0.000693% 11/1,587,464 alleles · ultra-rare exomes 4/1,435,208 · genomes 7/152,256 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IP6K2
Protein: p.Leu33Phe
Coding: c.97C>T
MANE Select: NM_016291
dbSNP: rs375230535
Type: single nucleotide variant
Location: chr3:48695195 (GRCh38)
Gene constraint: LOEUF 0.385 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.92

Full IP6K2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IP6K2 p.Ala195Gly Uncertain significance ★ ⚠ same type
IP6K2 p.Ala374Val Uncertain significance ★ ⚠ same type
IP6K2 p.Ala57Thr Uncertain significance ★ ⚠ same type
IP6K2 p.Arg133Cys Uncertain significance ★ ⚠ same type
IP6K2 p.Arg133His Uncertain significance ★ ⚠ same type
IP6K2 p.Arg198Gln Uncertain significance ★ ⚠ same type
IP6K2 p.Arg198Trp Uncertain significance ★ ⚠ same type
IP6K2 p.Arg212Cys Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ip6k2-p-leu33phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown